The immunogenicity of the tumor-associated antigen Lewisy may be suppressed by a bifunctional cross-linker required for coupling to a carrier protein
The immunogenicity of the tumor-associated antigen Lewisy may be suppressed by a bifunctional cross-linker required for coupling to a carrier protein
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DOI：
10.1002/chem.200400074
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发表时间：
2004-07-19
影响因子：
4.3
通讯作者：
Boons, GJ
中科院分区：
文献类型：
--
作者：
Buskas, T;Li, YH;Boons, GJ
以乙酰丙酯和9-荧甲氧基碳酸酯为羟基临时保护基，以三氯乙氧羰基为氨基保护基，采用高度收敛的方法合成了氨丙基修饰的Lewis(Y)(Le(Y))四糖。人工氨丙基部分被硫代乙酰基修饰，从而与亲电的4-(马来酰亚胺甲基)环己烷-1-羧酸酯(MI)修饰的锁孔帽状血蓝蛋白(KLH)发生有效的偶联。用KLH-MI-Le(Y)抗原免疫小鼠。通过对血清进行详细的ELISA法分析，证实了针对该连接区的免疫球蛋白G(Ig G)抗体应答。使用更小和更灵活的3-(溴乙酰胺)丙酸酯将Le(Y)连接到KLH上，不仅降低了对接头的抗体应答，而且显著提高了对Le(Y)抗原的免疫应答。这项研究表明，高抗原性连接物抑制了对弱抗原(如自身抗原)的抗体反应。
A Lewis(y) (Le(y)) tetrasaccharide modified by an artificial aminopropyl spacer was synthesized by a highly convergent approach that employed a levulinoyl ester and a 9-fluorenylmethoxycarbonate for temporary protection of the hydroxy groups and a trichloroethyloxycarbonyl as an amino protecting group. The artificial aminopropyl moiety was modified by a thioacetyl group, which allowed efficient conjugation to keyhole limpet hemocyanin (KLH) modified by electrophilic 4-(maleimidomethyl)cyclohexane-1-carboxylate (MI). Mice were immunized with the KLH-MI-Le(y) antigen. A detailed analysis of sera by ELISA established that a strong immunoglobulin G (IgG) antibody response was elicited against the linker region. The use of a smaller and more flexible 3-(bromoacetamido)propionate for the attachment of Le(y) to KLH not only reduced the IgG antibody response against the linker but also led to a significantly improved immune response against the Le(y) antigen. This study shows that highly antigenic linkers suppress antibody responses to weak antigens such as self-antigens.